Impact of type of anticoagulant on clinical outcomes in cancer patients who had atrial fibrillation

To date, evidence on optimal anticoagulant options in patients with AF who concurrently have active cancer remains elusive. To describe anticoagulant patterns and clinical outcomes among patients with a concomitant diagnosis of AF and cancer. Data were obtained from the University of Utah and Huntsman Cancer Institute (HCI) Hospitals. Patients were included if they had diagnosis of AF and cancer. Outcome was type and pattern of anticoagulant. Clinical outcomes were stroke, bleeding and all-cause mortality. From October 1999 to December 2020, there were 566 AF patients who concurrently had active cancer. Mean age ± standard deviation was 76.2 ± 10.7 and 57.6% were males. Comparing to warfarin, patients who received direct oral anticoagulant (DOACs) were associated with similar risk of stroke (adjusted hazard ratio, aHR 0.8, 95% confidence interval [CI] 0.2–2.7, P = 0.67). On contrary, those who received low-molecular-weight heparin (LMWH) were associated with significantly higher risk of stroke comparing to warfarin (aHR 2.4, 95% CI 1.0–5.6, P = 0.04). Comparing to warfarin, DOACs and LMWH was associated with similar risk of overall bleeding with aHR 1.1 (95% CI 0.7–1.6, P = 0.73) and aHR 1.1 (95% CI 0.6–1.7, P = 0.83), respectively. Patients who received LMWH but not DOACs were associated with increased risk of death as compared to warfarin, aHR 4.5 (95% CI 2.8–7.2, P < 0.001) and 1.2 (95% CI 0.7–2.2, P = 0.47). In patients with active cancer and AF, LMWH, compared to warfarin, was associated with an increased risk of stroke and all-cause mortality. Furthermore, DOACs was associated with similar risk of stroke, bleeding and death as compared to warfarin.

www.nature.com/scientificreports/ with AF who concurrently have active cancer remains elusive. Existing clinical guidelines on prevention VTE in AF patients do not provide recommendations for patients with AF and active cancer.
To address this information gap, we proposed to utilize real-world data to describe anticoagulation treatment patterns and identify the appropriate pharmacological treatment options based on drug interactions between anticoagulants, especially DOACs, and neoplastic agents and also based on the clinical outcomes associated with each anticoagulant treatment.

Materials and methods
Data source. Data used in this study were obtained from the University of Utah and Huntsman Cancer Institute (HCI) Hospitals which are major health centers serving the Intermountain West region. The University of Utah health system and HCI's tumor registry provide a rich data source, the Electronic data warehouse (EDW), which is maintained by the University of Utah Health Science Data Resource Center. The EDW contains a broad range of clinical data from more than 2 million patients, such as patients' demographics, clinical encounters, disease diagnoses, medical procedures and treatments, lab tests, list of medications, physicians' notes, and health outcomes.
Patients. Patients were included in the study if they were aged 18 years old and older, had a diagnosis of AF defined as having at least two diagnosis code of ICD-9 or ICD-10 encounters suggestive of atrial fibrillation (I48.x) within the study period, use of at least one anticoagulation therapy (i.e. warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, enoxaparin, dalteparin, or tinzaparin), and had any neoplasm diagnosis defined as having at least two diagnosis code of ICD-9 or ICD-10 encounters suggestive of cancer (C00.x-D49.x) within the study period. Patients with valvular AF were not included. Cancer patients who did not receive anticoagulant at the date of cancer diagnosis were excluded from the study.
Data collection. We collected the following data; patient demographics, type and primary site of cancer, date of cancer diagnosis, date of AF diagnosis, CHA 2 DS 2 -VASc score, serum creatinine and creatinine clearance, medical history included previous ischemic heart disease, stroke, peripheral arterial disease, diabetes, hypertension, dyslipidemia and chronic kidney disease. Medical history in individual patients was retrieved using ICD-9 or ICD-10 codes for any of these conditions in the 6 months prior to the cancer diagnosis. Index date was the date when patients were firstly diagnosed with cancer. We collected all anticoagulants prescribed in individual patients. The date of starting, switching, and of stopping anticoagulant was collected.
Outcomes. The primary outcome of interest was type of anticoagulant prescription before and after the diagnosis of cancer in individual patients. We divided patients into 4 groups according to the pattern of anticoagulant prior to index date of cancer diagnosis; group 1 patients who did not receive anticoagulant therapy (no anticoagulant group), group 2 patients who received warfarin before cancer diagnosis (warfarin group), group 3 patients who received DOACs before cancer diagnosis (DOAC group) and group 4 patients who received either LMWH or UFH (LMWH/UFH group) before cancer diagnosis.
The primary clinical outcomes were the occurrence of stroke after index date of cancer diagnosis. The secondary clinical outcomes were bleeding (gastrointestinal bleeding, intracranial bleeding and other bleeding) that required hospitalization, and all-cause mortality. Stroke and bleeding events were identified using ICD-9 or ICD-10 codes which occurred following the index date. Statistical analysis. Descriptive statistics were used to summarize patient characteristics and treatment patterns in the cohort. Mean and standard deviation were used to report continuous variables. Frequency and percentages were used to report categorical variables.
Patients in the cohort were followed up until they developed a clinical outcome of interest or until the end of study period, whichever came first. Patients who did not develop a clinical outcome of interest or whose last encounter was identified by the end of the study period were considered censored.
Given that patients were likely to switch anticoagulants during the follow-up period, we conducted the primary analysis using marginal structural models (MSM). The MSM is a statistical technique that accounts for potential biases introduced by time-dependent confounders when analyzing the effect of time-varying exposures on outcomes 10,11 . In our cohort, patients experienced changes in clinical variables, such as serum creatinine, body weight, or hemoglobin, which could act as potential confounding variables. These changes were likely to affect the type of anticoagulant received. To implement the MSM, we assigned weights to each participant at each time point based on their anticoagulant exposure history. These weights were used to balance the influence of time-varying confounders, thus enabling a more accurate estimation of the treatment effect on the outcome. We then calculated inverse probability weights (IPWs) by taking the inverse of the estimated propensity score, representing the conditional probability of receiving a particular exposure given the participants' covariates. Subsequently, we performed a weighted outcome analysis, incorporating the individual-specific weights, using the Cox proportional hazard model to estimate the causal effect of the exposure on the outcome 10,11 . Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. The events were presented as events per 100 patient-years. We compared the risk of developing outcomes across all types of anticoagulants. The sensitivity analysis was performed by excluding participants who were enrolled before 2010 (DOAC was not yet approved for stroke and systemic embolism prevention in AF patients). All analyses were conducted using STATA version 15

Results
From October 1999 to December 2020, a total of 566 patients with AF who were concurrently diagnosed with active cancer were included in this study. The median follow-up duration was 48.9 months (interquartile range 22.2-73.9 months). A summary of the clinical characteristics of the patients is presented in Table 1. The mean age of the participants was 76.2 years, with a standard deviation (SD) of 10.7. Among the included patients, 326 were males, accounting for 57.6% of the cohort. The mean CHA 2 DS 2 -VASc Score was 4.4 (SD 2.0). It was observed that patients who received LMWH/UFH at the time of cancer diagnosis were slightly younger and had a higher likelihood of having chronic kidney disease compared to those who were treated with warfarin or DOAC.
Pattern of anticoagulant prescription. Figure 1

Overall bleeding.
Overall bleeding occurred at rates of 11.5, 14.2 and 24.8 events per 100 patient-years in patients who received warfarin, DOACs and LMWH/UFH, respectively ( Table 2). Univariable analysis revealed that primary GI cancer was associated with increased risk of overall bleeding, HR 2.0 (95% CI 1.3-3.0, P = 0.02).
We conducted a sensitivity analysis by excluding participants who were enrolled before 2010. The results of this analysis remained consistent with the findings of the primary analysis for all outcomes. (data not shown).

Discussion
The optimal anticoagulant strategy in patients with cancer who also have AF remains controversial. This study demonstrates that anticoagulants might be switched after cancer diagnosis. We observed an increased risk for stroke and all-cause mortality in patients using LMWH/UFH compared to warfarin. Previously, a retrospective study of 472 cancer patients with electrocardiography-documented AF or atrial flutter (AFL) revealed that 44.3% of patients did not receive stroke prevention with anticoagulant therapy 12 . Likewise, in a prospective study of 4664 cancer patients, 394 of which had documented AF 13 , only 40% of AF patients received anticoagulant. These investigators found that anticoagulant treatment was not significantly related to mortality 13 . Possible reasons for this concerning lack of prescribing anticoagulant therapy for more than half of cancer patients who had AF may have included current chemotherapy use, prior bleeding, and comorbid conditions 12 . Figure 1. Pattern of anticoagulant use in cancer patients with atrial fibrillation. Group 1 patients who did not received anticoagulant, group 2 patients who received warfarin before cancer diagnosis, group 3 patients who received DOACs before cancer diagnosis and group 4 patients who received LMWH/UFH before cancer diagnosis. NO AC no anticoagulant, DOAC direct oral anticoagulant, LMWH low-molecular-weight heparin, UFH unfractionated heparin. Table 2. Clinical outcomes in atrial fibrillation patients who had active cancer. GI gastrointestinal, DOAC direct oral anticoagulant, LMWH low-molecular-weight heparin, UFH unfractionated heparin, PY patientyears, HR hazard ratio, aHR adjusted subdistribution hazard ratio, CI confidence interval. www.nature.com/scientificreports/ Our observations indicated that patients who initiated anticoagulant therapy after their cancer diagnosis were more likely to receive LMWH/UFH compared to warfarin or DOACs. Conversely, individuals who were already on anticoagulant treatment before their cancer diagnosis were more inclined to continue with the same anticoagulant regimen.

Stroke
Patients with cancer may be more likely to be prescribed LMWH because it is preferred for treatment of VTE in this patient population 14 . However, evidence supporting the use of LMWH as a prophylaxis for stroke prevention in any patient with AF is scanty. Our main finding shows that patients who were prescribed LMWH or UFH (LMWH/UFH group) had a fourfold increased risk of stroke as compared to warfarin. The use of DOACs did not significantly increase risk of stroke compared to warfarin.
This finding was consistent with results from a prospective multicenter registry that included a total of 320 patients with active cancer and also had AF. Of these 192 patients were treated with DOACs and 110 patients with LMWH 15 . Stroke or systemic embolism occurred 1.0% per year in the DOACs group and 7.2% per year in LMWH group (P < 0.05). The bleeding rate was not statistically different between two groups 15 . This study emphasized that the use of LMWH might not be optimal for the prevention of stroke in cancer patient with AF.
The evidence supporting DOACs for stroke prevention in patients with cancer and AF is not strong because most patients with cancer were excluded from pivotal studies 16 . Post-hoc analysis of data from ENGAGE AF-TIMI 38 study included 1153 patients with AF who had new or recurrent malignancy 17 . The annualized stroke and systemic embolism rate was 1.4% per year in patients who received edoxaban 60 mg once daily, 2.0% per year in patients who received edoxaban 30 mg once daily, and 2.4% per year in those who received warfarin 17 . There was no statistical difference in efficacy between both doses of edoxaban and warfarin 17 18 .
Our study found that patients with cancer who also had AF and received any type of anticoagulant had an increased risk of bleeding. However, there was no statistical difference between bleeding rates in patients receiving either DOACs or LMWH/UFH as compared to warfarin. These findings were consistent with post-hoc analyses of the ENGAGE AF-TIMI 38 and ARISTOTLE trials which reported comparable bleeding rates between cancer patients who received DOACs (edoxaban or apixaban) vs. warfarin 17,18 . We also found that patients with primary GI cancer and CNS cancer were more likely to have GI and CNS bleeding, respectively. Data from pivotal trials in patients with cancer associated venous thrombosis showed that patients using edoxaban and rivaroxaban but not apixaban had increased risk of major bleeding as compared to LMWH, especially patients with GI or GU cancer [19][20][21] . However, an analysis of a medical record database in Taiwan demonstrated that the use of DOACs was associated with similar risk for major bleeding compared with LMWH 22 . The findings from real-world evidence may better reflect the appropriateness of anticoagulant choice in individual patients with different underlying bleeding risks.
The risk of death from any cause in our study was fourfold higher in the group prescribed LMWH/UFH compared to those prescribed warfarin. The death rate for warfarin and DOACs observed in our study was comparable from a post-hoc analysis of the ARISTOTLE trial in patients with AF who had cancer, which reported 4.7 and 3.6 deaths per 100 patient-years in patients who received apixaban and warfarin, respectively 18 . The reasons underlying the higher death rate associated with LMWH/UFH in our study were unclear but might be explained from patients' underlying conditions or anticoagulant effectiveness.
One of the strengths of this study is that it provided real-world data on the usage of anticoagulants among cancer patients who also have atrial fibrillation, both prior to and following a cancer diagnosis.
Our study has some limitations. First, we did not perform subgroup analysis by the four different types of DOACs because of the small numbers of patients in each category. Second, we did not include cancer patients with AF who did not receive anticoagulant therapy. Therefore, we could not compare the risk of stroke/systemic embolism and bleeding between these two groups. Third, the use of anticoagulant was based on prescription records. Therefore, we could not estimate the compliance rate and impact of compliance on outcomes. Fourth, given the retrospective nature of our data collection, we encountered limitations in obtaining comprehensive data required to classify the severity of bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) guideline 23 . However, it is important to note that the bleeding outcomes we captured were of sufficient severity to necessitate hospitalization, which we considered clinically relevant. Finally, the participants were enrolled between 1999 and 2020. Considering that DOACs were approved for the prevention of stroke and systemic embolism in 2010, patients enrolled during that period were more likely to receive warfarin treatment. However, it is important to note that the proportion of patients from that specific period was relatively small. Moreover, the sensitivity analysis conducted after excluding those patients yielded results consistent with the primary analysis.

Conclusions
This study found that LMWH/UFH, compared to warfarin in cancer patients with AF, was associated with increased risk of stroke. Furthermore, DOACs was associated with similar risk of stroke and bleeding as compared to warfarin. Based on our findings, we recommend caution in the use of LMWH/UFH in cancer patients with AF. Further prospective trials are needed to confirm these findings.

Data availability
The datasets generated and/or analysed during the current study are not publicly available due to institutional restriction but are available from the corresponding author on reasonable request.